Objective

Allogeneic bone marrow transplantation (BMT) may be more effective than autologous BMT as a treatment for patients with severe autoimmune diseases, such as rheumatoid arthritis (RA). However, the application of allogeneic BMT for treatment of RA is not yet feasible because of the high-dose immunosuppression that is used before and after BMT. Therefore, in this study collagen-induced arthritis (CIA) – the classic mouse model for RA – was used to compare the effects of allogeneic and syngeneic BMT after less toxic, nonlethal (i.e. nonmyeloablative) conditioning regimens on established disease in DBA/1 (H-2q) mice.

Methods

We induced arthritis in normal DBA/1 (H-2q) mice by immunization with type II collagen (CII) in complete Freund's adjuvans (CFA). To allow engraftment, we made use of anti-CD40 ligand monoclonal antibody (one injection of 0.5 mg ip) and nonlethal total body irradiation (TBI) of 6.0 Gy before BMT with 1.0 × 10e7 total BM cells from syngeneic DBA/1 (H-2q) mice or from fully MHC-mismatched allogeneic BALB/c (H-2d) mice. After treatment, mice were scored for clinical arthritis, and serum was taken to measure the amounts of CII-specific antibodies.

Results

We were able to induce stable and long-term (> 300 days) donor chimerism (> 95%) after transplantation with fully MHC-mismatched total BM cells from allogeneic BALB/c (H-2d) mice using a nonmyeloablative conditioning regimen. After initial exarcebation of arthritis shortly after allogeneic BMT, due to a graft-versus-host (GvH)/host-versus-graft (HvG) response, mice receiving allogeneic BM cells showed a significant suppression of arthritis and CII-specific antibodies. Syngeneic BMT was also effective in suppressing clinical disease, although no effects on CII-specific antibodies could be observed.

Conclusion

These data indicate that nonmyeloablative conditioning using low-dose TBI and anti-CD40 ligand monoclonal antibody followed by MHC mismatched allogeneic BMT results in donor chimerism, disappearence of pathogeneic autoantibodies and improvement in disease activity.